INSULIN SECRETORY RESPONSES AND PHOSPHOLIPID COMPOSITION OF PANCREATIC ISLETS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Studies involving pharmacologic or molecular biologic manipulation of Group VIA phospholipase A2 (iPLA2) activity in pancreatic islets and insulinoma cells suggest that iPLA2 participates in insulin secretion. It has also been suggested that iPLA2 is a housekeeping enzyme that regulates cell 2-lysophosphatidylcholine (LPC) levels and arachidonate incorporation into phosphatidylcholine (PC). We have generated iPLA2-null mice by homologous recombination and have reported that they exhibit reduced male fertility and defective motility of spermatozoa. Here we report that pancreatic islets from iPLA2-null mice have impaired insulin secretory responses to D-glucose and forskolin. Electrospray ionization mass spectrometric analyses indicate that the abundance of arachidonate-containing PC species of islets, brain, and other tissues from iPLA2-null mice is virtually identical to that of wild-type mice, and no iPLA2 mRNA was observed in any tissue from iPLA2-null mice at any age. Despite the insulin secretory abnormalities of isolated islets, fasting and fed blood glucose concentrations of iPLA2-null and wild-type mice are essentially identical under normal circumstances, but iPLA2-null mice develop more severe hyperglycemia than wild-type mice after administration of multiple low doses of the -cell toxin streptozotocin, suggesting an impaired islet secretory reserve. A high fat diet also induces more severe glucose intolerance in iPLA2-null mice than in wild-type mice, but PLA2-null mice have greater responsiveness to exogenous insulin than do wild-type mice fed a high fat diet. These and previous findings thus indicate that iPLA2-null mice exhibit phenotypic abnormalities in pancreatic islets in addition to testes and macrophages.